CN103880674A - Synthetic process of L-menthyl glyoxylate - Google Patents
Synthetic process of L-menthyl glyoxylate Download PDFInfo
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- CN103880674A CN103880674A CN201410116089.8A CN201410116089A CN103880674A CN 103880674 A CN103880674 A CN 103880674A CN 201410116089 A CN201410116089 A CN 201410116089A CN 103880674 A CN103880674 A CN 103880674A
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- menthol
- glyoxylic
- glyoxylic ester
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for preparing L-menthyl glyoxylate. The method comprises the steps of 1) adding an organic solvent, a reactant L-menthol, a 50% glyoxylic acid aqueous solution, 4-dimethylaminopyridine to a reactor and stirring at a room temperature for 1 hour, 2) in an ice bath, dropwise adding the organic solvent solution of dicyclohexylcarbodiimide to the mixture within 1 to 2 hours, increasing the temperature to the room temperature and stirring for 1 hour, heating for reflux, separating out water, calculating the volume of the water and stirring for 10-12 hours, 3) washing by using a hydrochloric acid aqueous solution, a sodium hydroxide aqueous solution and a saturated salt solution, respectively, and then carrying out drying, filtering, spin-drying and recrystallizing to obtain the product L-menthyl glyoxylate. The method is stable and safe in reaction, high in yield, low in cost, simple in process and easy to industrialize.
Description
Technical field
The invention belongs to fine chemical technology field, be specifically related to a kind of preparation method of MENTHOL glyoxylic ester.
Background technology
MENTHOL glyoxylic ester is white powder, and fusing point 77-79 ℃, as the synthetic intermediate of antiviral drug lamivudine, emtricitabine, is also an important chirality source compound during chirality is synthesized.
The synthetic technology of MENTHOL glyoxylic ester is reported in many pieces of documents, mainly comprises following a few example but can realize industrialized technique:
(1) tartrate and MENTHOL are carried out to esterification, synthetic tartrate two menthol esters, generate MENTHOL glyoxylic ester (Synthetic Commun. by periodate oxidation again, 1990,20,2837), this technology yield is higher, but Periodic acid is more expensive, production cost is higher, and this technique is eliminated;
(2) using the vitriol oil is catalyzer, divide water esterification by the aqueous glyoxylic acid azeotropic of excessive MENTHOL and 50% concentration, the MENTHOL glyoxylic ester obtaining is through adding aqueous solution of sodium bisulfite to form its adducts hydroxy sulfonate, after separation, add again formalin hydrolysis and obtain MENTHOL glyoxylic ester hydrate (DE443567A1,1995).The shortcoming of this method is that concentrated sulfuric acid catalyst makes raw material easily oxidized in dehydration reaction process, by product is many, subsequent disposal is numerous and diverse, and equipment is had to powerful corrodibility, spent acid causes the problems such as environmental pollution, and patent CN101274892A changes catalyzer into solid acid, other term harmonizations, the formation of by product and the discharge of spent acid are reduced, but in reaction, MENTHOL raw material is greatly excessive, reclaim that raw material is applied mechanically because byproducts build-up, product yield can reduce along with applying mechanically increased frequency, and quality also can decline thereupon;
(3) MENTHOL and a halogen or dihalo-carboxylic acid halides or anhydride reaction generate a halogen or two halogen acetic acid MENTHOL esters, the reaction solution that is raw material with a halogen acetic acid MENTHOL ester, after cooling through dilution, P
2o
5dMSO solution and triethylamine processing, obtain MENTHOL glyoxylic ester; Or the reaction solution that is raw material with two halogen acetic acid MENTHOL esters, through washing, extraction, concentrates and obtains MENTHOL glyoxylic ester, obtains its monohydrate (CN102516078A) by sodium bisulfite and formaldehyde treated.The shortcoming second step yield of this method is lower, and cost is higher.
Summary of the invention
The object of this invention is to provide a kind of method of producing MENTHOL glyoxylic ester, the purity of MENTHOL glyoxylic ester is improved, stable reaction, safety, improve product yield, reduces costs.
The present invention solves the problems of the technologies described above by the following technical solutions, reaches object of the present invention.A method for synthetic MENTHOL glyoxylic ester, comprises the following steps:
1) in reactor, add organic solvent, reactant MENTHOL, 50% aqueous glyoxylic acid, DMAP, stirring at room temperature 1 hour;
2) under ice bath, to the organic solvent solution that drips dicyclohexylcarbodiimide in said mixture, within 1～2 hour, drip off, rise to stirring at room temperature 1 hour, reflux, point water, calculates the volume of water, stirs 10～12 hours;
3) use respectively aqueous hydrochloric acid, aqueous sodium hydroxide solution, saturated common salt water washing, be dried, filter, be spin-dried for, recrystallization, obtain MENTHOL glyoxylic ester product.
In described step 1), described organic solvent is normal heptane, hexanaphthene, toluene, is preferable over hexanaphthene; With the mass ratio of MENTHOL be 5～8:1.
In described step 1), reactant MENTHOL: 50% aqueous glyoxylic acid: the mol ratio of DMAP is 1:1.1～2:0.02～0.05.
Described step 2) in, the mol ratio of reactant MENTHOL and dicyclohexylcarbodiimide is 1:0.9～1.1, is preferable over 1:1.
Described step 2) in, described organic solvent is normal heptane, hexanaphthene, toluene, is preferable over hexanaphthene; With the mass ratio of MENTHOL be 2～4:1.
Described step 2) in, in controlling when reflux, temperature is at 95-102 ℃.
In described step 3), the volumetric molar concentration of aqueous hydrochloric acid is that the mass concentration of 1mol/L, aqueous sodium hydroxide solution is 10g/L.
In described step 3), be alcohol-water from crystallization solvent used, MENTHOL glyoxylic ester: ethanol: the mass ratio of water is 1:5:2.
The present invention adopts safety, economic solvent and catalyzer to synthesize MENTHOL glyoxylic ester, and the MENTHOL glyoxylic ester synthetic method craft providing is simple, safe ready, mild condition, yield reaches more than 85%, and reaction solvent used can be recycled, and easily realizes suitability for industrialized production.
Embodiment
Below embodiments of the invention are elaborated: the present embodiment is implemented under take technical solution of the present invention as prerequisite, provided at length embodiment and process, but protection scope of the present invention is not limited to following embodiment.
Embodiment 1
In reactor, add reactant MENTHOL 156g, 50% aqueous glyoxylic acid 175ml, DMAP 3g, hexanaphthene 500ml stirring at room temperature 1 hour, under ice bath, to the hexanaphthene mixing solutions that drips 206g dicyclohexylcarbodiimide and 200ml in said mixture, within 1～2 hour, drip off, rise to stirring at room temperature 1 hour, reflux, in controlling, temperature is at 95-102 ℃, divide water, calculate the volume of water, stir 10～12 hours, use respectively aqueous hydrochloric acid 300ml, aqueous sodium hydroxide solution 300ml, the each organic phase of all washing at twice of saturated aqueous common salt 300ml, anhydrous sodium sulfate drying organic phase, filter, be spin-dried for, obtain 215g MENTHOL glyoxylic ester crude product, carry out recrystallization with 1L ethanol and 400ml water, obtain the MENTHOL glyoxylic ester 200g that purity is greater than 98%, fusing point is 76-78 ℃, yield is 86.9%.
Embodiment 2
In reactor, add reactant MENTHOL 156g, 50% aqueous glyoxylic acid 175ml, DMAP 3g, toluene 400ml stirring at room temperature 1 hour, under ice bath, to the toluene mixing solutions that drips 206g dicyclohexylcarbodiimide and 200ml in said mixture, within 1～2 hour, drip off, rise to stirring at room temperature 1 hour, reflux, in controlling, temperature is at 100-105 ℃, divide water, calculate the volume of water, stir 10～12 hours, use respectively aqueous hydrochloric acid 300ml, aqueous sodium hydroxide solution 300ml, the each organic phase of all washing at twice of saturated aqueous common salt 300ml, anhydrous sodium sulfate drying organic phase, filter, be spin-dried for, obtain 205g MENTHOL glyoxylic ester crude product, carry out recrystallization with 1L ethanol and 400ml water, obtain the MENTHOL glyoxylic ester 190g that purity is greater than 98%, fusing point is 76-78 ℃, yield is 82.6%.
Embodiment 3
In reactor, add reactant MENTHOL 156g, 50% aqueous glyoxylic acid 125ml, DMAP 3g, hexanaphthene 500ml stirring at room temperature 1 hour, under ice bath, to the hexanaphthene mixing solutions that drips 206g dicyclohexylcarbodiimide and 200ml in said mixture, within 1～2 hour, drip off, rise to stirring at room temperature 1 hour, reflux, in controlling, temperature is at 95-102 ℃, divide water, calculate the volume of water, stir 10～12 hours, use respectively aqueous hydrochloric acid 300ml, aqueous sodium hydroxide solution 300ml, the each organic phase of all washing at twice of saturated aqueous common salt 300ml, anhydrous sodium sulfate drying organic phase, filter, be spin-dried for, obtain 200g MENTHOL glyoxylic ester crude product, carry out recrystallization with 1L ethanol and 400ml water, obtain the MENTHOL glyoxylic ester 180g that purity is greater than 98%, fusing point is 76-78 ℃, yield is 78.3%.
Claims (7)
1. the present invention is specifically related to a kind of method of synthetic MENTHOL glyoxylic ester, it is characterized in that comprising the steps:
1) in reactor, add organic solvent, reactant MENTHOL, 50% aqueous glyoxylic acid, DMAP, stirring at room temperature 1 hour;
2) under ice bath, to the organic solvent solution that drips dicyclohexylcarbodiimide in said mixture, within 1～2 hour, drip off, rise to stirring at room temperature 1 hour, reflux, point water, calculates the volume of water, stirs 10～12 hours;
3) use respectively aqueous hydrochloric acid, aqueous sodium hydroxide solution, saturated common salt water washing, be dried, filter, be spin-dried for, recrystallization, obtain MENTHOL glyoxylic ester product.
2. produce as described in claim 1 the method for MENTHOL glyoxylic ester, in described step 1), described organic solvent is normal heptane, hexanaphthene, toluene, is preferable over hexanaphthene; With the mass ratio of MENTHOL be 5～8:1.
3. produce as described in claim 1 the method for MENTHOL glyoxylic ester, in described step 1), reactant MENTHOL: 50% aqueous glyoxylic acid: the mol ratio of DMAP is 1:1.1～2:0.02～0.05.
4. produce as described in claim 1 the method for MENTHOL glyoxylic ester, described step 2) in, the mol ratio of reactant MENTHOL and dicyclohexylcarbodiimide is 1:0.9～1.1, is preferable over 1:1.
5. produce as described in claim 1 the method for MENTHOL glyoxylic ester, described step 2) in, described organic solvent is normal heptane, hexanaphthene, toluene, is preferable over hexanaphthene; With the mass ratio of MENTHOL be 2～4:1.
6. produce as described in claim 1 the method for MENTHOL glyoxylic ester, described step 2) in, in controlling when reflux, temperature is at 95-102 ℃.
7. producing as described in claim 1 the method for MENTHOL glyoxylic ester, in described step 3), is alcohol-water from crystallization solvent used, MENTHOL glyoxylic ester: ethanol: the mass ratio of water is 1:5:2.
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| CN201410116089.8A CN103880674A (en) | 2014-03-27 | 2014-03-27 | Synthetic process of L-menthyl glyoxylate |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107382725A (en) * | 2016-05-16 | 2017-11-24 | 江苏普信制药有限公司 | A kind of method of continuous production dihydroxy acetic acid MENTHOL ester |
| CN112341336A (en) * | 2019-08-06 | 2021-02-09 | 上海迪赛诺生物医药有限公司 | Method for preparing MGH by using reaction of aldehyde sodium sulfite and MGH esterification liquid |
| CN115386028A (en) * | 2022-08-26 | 2022-11-25 | 长春理工大学 | Polymerization degree controllable polysorbate-D-menthol ester and synthesis method and application thereof |
| CN115772084A (en) * | 2022-11-28 | 2023-03-10 | 艾美科健（中国）生物医药有限公司 | Preparation method of cefotaxime side chain intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101274892A (en) * | 2008-05-04 | 2008-10-01 | 浙江教育学院 | Method for preparing L-menthol glyoxylic ester monohydrate with solid acid as catalyst |
| JP4361359B2 (en) * | 2003-12-12 | 2009-11-11 | 高砂香料工業株式会社 | Method for producing glyoxylate ester |
-
2014
- 2014-03-27 CN CN201410116089.8A patent/CN103880674A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4361359B2 (en) * | 2003-12-12 | 2009-11-11 | 高砂香料工業株式会社 | Method for producing glyoxylate ester |
| CN101274892A (en) * | 2008-05-04 | 2008-10-01 | 浙江教育学院 | Method for preparing L-menthol glyoxylic ester monohydrate with solid acid as catalyst |
Non-Patent Citations (4)
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| 丁盈红等: "水杨酸苯酯的合成新方法研究", 《山西化工》 * |
| 佘志刚等: "DMAP催化合成苯甲酸苯酯的研究", 《化学试剂》 * |
| 许友: "顺丁烯二酸二异辛酯合成新方法", 《湖南理工学院学报》 * |
| 麦尔布哈•阿不都热西提: "溴苯薄荷醇衍生物和联苯薄荷醇衍生物的合成表征", 《西南师范大学学报》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107382725A (en) * | 2016-05-16 | 2017-11-24 | 江苏普信制药有限公司 | A kind of method of continuous production dihydroxy acetic acid MENTHOL ester |
| CN112341336A (en) * | 2019-08-06 | 2021-02-09 | 上海迪赛诺生物医药有限公司 | Method for preparing MGH by using reaction of aldehyde sodium sulfite and MGH esterification liquid |
| CN115386028A (en) * | 2022-08-26 | 2022-11-25 | 长春理工大学 | Polymerization degree controllable polysorbate-D-menthol ester and synthesis method and application thereof |
| CN115772084A (en) * | 2022-11-28 | 2023-03-10 | 艾美科健（中国）生物医药有限公司 | Preparation method of cefotaxime side chain intermediate |
| CN115772084B (en) * | 2022-11-28 | 2024-04-09 | 艾美科健（中国）生物医药有限公司 | Preparation method of cefvicin side chain intermediate |
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Application publication date: 20140625 |